Mark Dewhirst, DVM, PhD, FASTRO
Dr. Montana: On behalf of the History Committee Dr. Ted Lawrence and I will be interviewing Dr. Mark Dewhirst a long standing and very distinguished radiation biologist and member of our society. Mark has made very significant contributions to radiation biology, to the understanding of cancer and to radiation oncology in general. For me it is a distinct honor and privilege to interview Mark, a very valued fellow faculty member of the Duke Radiation Oncology Department and a dear friend. I also appreciate having the opportunity to interview Mark with Ted Lawrence. I shall begin by asking Mark, about your background.
Dr. Dewhirst: Okay. Well, I was born in what's called the “little apple”, which is Manhattan, Kansas, in 1949. My father was a graduate student at that time in animal sciences. After he received his PhD, we moved to a Tucson. We moved to Tucson when I was 7 years old. I was in second grade I believe. I think of Tucson as my hometown. I grew up there and went to high school. Since my father was on the faculty of the University of Arizona in Tucson, Arizona, I had the options to go to one of the schools in Arizona; this was strongly encouraged because faculty had a tuition benefit. I went to Northern Arizona University for a year and had a lot of fun up there, but I realized if I was going to do anything seriously, I needed to come back to Tucson and go to the University of Arizona. I spent the last three years at the University of Arizona and graduated from there in 1971, with a bachelor's degree in chemistry.
Dr. Lawrence: Did you do any research during your undergraduate work that got you interested in your future career or mainly stick with the course work?
Dr. Dewhirst: No. I did do research. I worked in several laboratories during that period of time, but having a father who is a scientist also stimulated me to be interested in research. He was in parasitology, and I can remember when I was five years old going out in the fields in Manhattan collecting fecal samples to look for worms. So I kind of got the bug, if you will.
Dr. Montana: Just like that.
Dr. Dewhirst: I did undergraduate research in the chemistry department. I also worked in the agronomy and plant pathology departments throughout my undergraduate studies.
Dr. Montana: And then you went to Colorado?
Dr. Dewhirst: I did. I actually started out as a pre-med in the chemistry department, and what I discovered was that the pre-meds there were a bit obnoxious.
Dr. Lawrence: Did you think about becoming a practicing veterinarian?
Dr. Dewhirst: No. When I applied I said I was interested in research. In fact, I was telling my father, when I decided to go, that I really thought that it would be interesting to study diseases in pet's as models for humans. I had no idea what I was talking about at the time, but it turned out to be a terrific career path.
Dr. Lawrence: I have always thought the best research degree was the veterinary degree, for that exact reason.
Dr. Dewhirst: So, I went to Colorado State and had a summer job working for Ed Gillette. That is what stimulated me to pursue a career in cancer research.
Dr. Lawrence: Ah, perfect.
Dr. Dewhirst: That’s how it happened, because up until that time I had lots of jobs and they were all kind of interesting. But when I started studying radiation oncology, and oncology in general, I knew I was hooked because I couldn't stop reading about it. It was the most interesting thing that I had ever done.
Dr. Montana: Was Ed at Colorado then?
Dr. Dewhirst: Yes, he was.
Dr. Montana: He died not too many years ago.
Dr. Dewhirst: Yes. Their department was certainly, I'd say, world famous. The department of radiation biology was in a position of prominence back in the 70s. The department was started in the early 1960s. So by the time I was there it was very well established and very well known.
Dr. Lawrence: I think it’s one of the best programs in the world in animal radiation biology and understanding, not just cells and culture, but actual patients.
Dr. Dewhirst: Yes. And that happened because Ed did a Sabbatical with Herman Suit. He was at MD Anderson. And Rod Withers was there at that time.
They had many discussions about how he could use pet animal tumors to learn more about radiation oncology. He took those ideas back to Colorado with a vision of creating an animal tumor center. I was in on it from the very beginning, along with Don Thrall and a third veterinarian, named Patrick Gavin. We were there at the very beginning of the animal tumor center. This was back when the other clinicians in the hospital who were doing oncology would hide patients from Ed, because they didn't want him to irradiate them. He had a bunch of undergraduate technicians that he hired, they would go cruise through the wards looking for potential cancer patient that could be treated with radiation therapy. We called them the “tumor beavers”. Now there is a specialty board for veterinary radiation oncology and it is a very well respected field. So times change that's for sure.
Dr. Montana: So Mark, you went back to Tucson, right?
Dr. Dewhirst: Yes, I did.
Dr. Lawrence: Wait a second, you did the veterinarian’s degree but then you decided to go graduate school, right?
Dr. Dewhirst: I did. I got a PhD at Colorado State, with Ed. And because I knew I wanted to do a PhD, and I had a family at that time, and I really liked Ed, and so it just seemed to be the right thing to do. So I stayed there and did a PhD with him. When I was in graduate school, a relatively famous radiation oncologist came to CSU on Sabbatical; his name was Max Boone. Max had been the prior chair of radiation oncology in Arizona. We were in the same lab working together and we struck up a friendship. He was one of the most brilliant men I've ever met. So when I decided to start looking for post docs, I interviewed at Washington University, with the guy named Fred Valleriote and George Hahn at Stanford. And then I interviewed with Max. I ended up going back to Arizona because of my friendship with Max and for economic reasons. They were willing to offer me a bit more money and I, again, had a family. But at the time, both Stanford and the Arizona group had program project grants in hyperthermia, and both programs were treating pets with cancer with heat.
Dr. Lawrence: You just answered my question on how you got started in hyperthermia.
Dr. Dewhirst: Yes. I was recruited to do this. I was always interested in the idea of running clinical trials in pets, particularly after I learned about veterinary oncology. I just thought it would be really interesting to do. So, it was a perfect job for me, I loved it. Over the five years that I was there in Arizona I ran a randomized trial. It was the first randomized trial comparing radiation therapy alone to radiation plus heat. I accrued 250 pets under that trial, in five years.
Dr. Montana: So, Jim Oleson was there at the time?
Dr. Dewhirst: Jim was there. That's how we met. It was a great time. Both Jim and I learned a lot by being a part of that program. Eugene Garner was head of it. Toward the end of the five years, though, I began to be very dissatisfied with the way it was arranged. It really had to deal with the fact that I was running an oncology practice out of a medical school with no infrastructure. A lot of these pets, as you can imagine, had other co-morbidities and I didn't have any support to help them with their other health problems. I was on call 24/7. It was just killing me. In the end I had to do something different. I approached the medical school about the idea of buying a clinical practice that was nearby and was up for sale. I proposed to upgrade it and do oncology trials at the facility. In doing so I could hire the right kind of people to help me. However, the medical school was not interested in that. So I started looking around for jobs. Ironically, Jim started looking for jobs at the same time. He wanted a job where he could have more authority over a research program. My wife and I happened to go over to Jim’s house for dinner one night. Just by chance, I happened to mention that I was looking to go elsewhere. Neither one of us knew at the time. So he said we should try to work it out so we could go together. I thought, “Yeah, sure, that will happen.”
Dr. Lawrence: That would’ve been difficult. Wow.
Dr. Dewhirst: That’s how it happened though. I interviewed at Wisconsin, which had a veterinary school and medical school on the same campus. I also interviewed at NIH for a job.
Dr. Montana: Eli was there at the time.
Dr. Dewhirst: But the Duke job was by far the most attractive. The package they put together for us was incredible. I was so impressed with the demeanor of the place and also their tremendous resources that they had, particularly in imaging.
Dr. Lawrence: Who was the chair at that time?
Dr. Montana: It was in transition at that time. Len had just come here to Duke.
Dr. Dewhirst: He was the division chief at that time
Dr. Montana: Len had already paved the way for it to become a department.
Dr. Dewhirst: Yes. He had just struck a deal that if he showed that he could make money they would let him create a separate department from radiology. That didn't take very long. Charles Putnam was the chair of radiology at that time.
Dr. Lawrence: Okay. So it was the chair of radiology who had recruited you into the section of radiation oncology, is that how it worked?
Dr. Dewhirst: Yes, into this division.
Dr. Montana: Dr. Putman, the chair of the radiology department here at Duke, had been the member of the radiology department at Yale, and knew Len Prosnitz well and was very influential in getting Len to come here to Duke to head the division of radiation oncology that became a department soon thereafter.
Dr. Dewhirst: Yes. That's how it happened. And then Len decided he wanted to build a world class research group. I think he thought about a lot of options at that time. And at that time, hyperthermia was pretty popular, so he recruited Jim. Jim said, “Well, I can't come unless Mark comes.” That's how I ended coming here.
Dr. Lawrence: So we're now around 1984, is that about right?
Dr. Dewhirst: Yes, I came here in 1984.
Dr. Lawrence: Yes, I'm looking at your CV and your first appointment actually was in the department of radiology, so this must be in the transition of radiation oncology becoming a new department.
Dr. Dewhirst: Right.
Dr. Lawrence: So you then just continued to work in hyperthermia.
Dr. Dewhirst: We built on what we did in Arizona through an incredibly large startup package that we got from the cancer center, the department and the dean. Our charge was to develop a program project grant. We started working on this goal in 1984, and got it funded in 1987.
Dr. Lawrence: That's very quick when it's from the ground up.
Dr. Montana: You also were successful in recruiting Thad Samulski around at that time.
Dr. Dewhirst: We did. We recruited Thad Samulski here and Scott Clegg who is another engineer. Thad was really a physicist, but we had Thad and Scott. Thad just absolutely fundamental in getting everything done because, although Jim Oleson had a background in engineering, he couldn't make machines run and do all the infrastructure for QA and QC and so forth.
Dr. Montana: Thad had been at a Stanford working in hyperthermia.
Dr. Dewhirst: Right. He worked with George Hahn.
Dr. Lawrence: I interviewed at the University of Arizona out of my residency in 1986, and Tom Cetas was still there. But they were still mourning the loss of you and Jim.
Dr. Dewhirst: I think the other key to the success of our program in the long run was our association with NC State. So we continued our work with spontaneous animal tumors up until our program stopped in 2009. The fact that we had access to these animal patients was really key because we were able to do so many things with them that we could just never do in human subjects. We learned so much. In a number of cases we have avoided running costly clinical trials in humans by finding out things in the pets and seeing clearly it wasn't going to work. I actually gave a lecture last weekend at the Veterinary Cancer Society meeting which was in Ashville. And they asked me to review that experience. It turned out, over those years, we published over 80 papers involving pets with cancer. I think it was 1,200 citations, or something like that. It's a tribute to what Ed Gillette taught both Don Thrall and I. I feel very proud of that part of my career. I really do.
Dr. Montana: One of the impressive things when you, Jim Oleson and Thad Samulski came here is that you did not operate as a separate division or enclave outside of the mainstream of the clinical practice. You were very present at the conferences and all functions of the department. You were all very receptive to medical students, residents, and junior members of the faculty. You all supported and encouraged everybody to engage in research.
Dr. Dewhirst: I felt it was very important. I used to go to the grand rounds all the time. The other thing I did, actually with Jim at the beginning, was to go into the clinic and shadowed Jim as he worked with patients, because I wanted to understand and support what they were going through. He actually helped with some of the dogs to, so it was kind of a cross-fertilization kind of thing.
And, and what I have to tell you which is anecdotal also, a couple of funny stories about that. One was that working with patients was first at first very disconcerting because they talked back to me. It was a strange feeling to have a patient talk to me when I walk into the room. It’s really funny, since I was a veterinarian, one patient was asking me if I was going to him a rabies shot.
We treated the first dog with cancer within a month of my arrival at Duke. It was a dog with prostate cancer and we did some heat and radiation treatment of this tumor. We used to have this cage which was covered up and was on wheels, and we’d put a sheet over it and we wheeled that dog into the area where the hyperthermia equipment was located. My technician opened the lid on that thing and walked away and then the dog, of course, jumps out. It ran down the hall into the middle of the waiting area, and here comes Len Prosnitz walking down the hall. I'm going, “Oh my God, he's gonna fire me.” The dog jumped up on his leg, wanting to be petted. Fortunately for me, Len liked dogs. We penned up the dog and put him back to where he belonged. I enjoyed being involved in the clinic and I felt like that was where I should be.
Dr. Montana: The basic sciences research program in our department at Duke exploded during that period of time. We always admired your ability to collaborate with people outside the department. Tell us more about that or some of the people that you began to develop research programs with.
Dr. Dewhirst: Thank you. At its height, the hyperthermia program had, I think, eight different departments involved across the medical school and the main campus. We had people from the engineering school as well as people from all kinds of the departments in the medical school. Pathology and a lot of radiology faculty. There were people from biomedical engineering, electrical engineering and microbiology. One of the things I used to do was to try to think outside the box, and invite other people to attend our research retreats. One of the things that came out of it was the idea that we might come up with a way to use heat to trigger drug delivery. I knew a guy who knew how to make liposomes. He was at the engineering school. I invited him to come during the retreat one time and I said, “It would be very interesting if you could make a liposome that was thermally sensitive in the clinically relevant temperature range.” This was an idea presented in literature already, but it was not practical, because the release temperature was too high. So he went back to his lab and invented a liposome that would actually release drug within the clinically relevant temperature range. I know you know about this Ted, because you handled the paper that we published in cancer research.
Dr. Lawrence: Yes, I did. It was really a beautiful paper. The reviewers really loved it.
Dr. Dewhirst: Oh, good. That was the real paradigm shift to just say that you could do something that would release drug inside the blood vessel. So, you kind of essentially have the equivalent of a local drug infusion in the tumor itself.
Dr. Lawrence: That leads to me next question. How did you go from hyperthermia to microvasculature. Because you've made so many contributions outside of hyperthermia, especially by developing the window chamber model to study the microvasculature. I wonder if you could talk about that a little bit and how you got into that.
Dr. Dewhirst: My own PhD thesis had to do with radiation effects on lymphocytes. And I went to Arizona with the express idea in mind that I was going to continue that work, but I hadn’t been there too long, and Gene Garner came to me and he said, “You are a veterinarian, right? Well, you must know some physiology.” I said, “Well, I took a course in vet school. I’m not an expert in physiology”. He said, “Well, I want you to meet this chemical engineer. His name is Joseph Gross. And he has this window chamber thing. He’s looking for somebody to help him with it.” Joe was a chemical engineer; he was really theoretician. He studied drug transport and did modelling and stuff like that. But he had taken the original Algire chamber and redesigned it to be made out of metal instead of plastics, so that it was resistant to crushing artifact that would artificially shut down blood flow. Joe made one out of anodized aluminum, and he co-engineered it with another guy. But he didn't have anybody to use it because he didn't know about biology really. So, I went over and I saw this thing and I thought to myself that “this was a freaking gold mine.” “If I don’t take this and do something with it, I'm just crazy.” I learned how to do the surgery. I went to California, to UCSD where there was a group that did a lot of intravital microscopy. That’s how I learned to do that. I then brought that technology back to Tucson and started working with it. Some of the initial work I did was actually looking in heat effects on perfusion and so forth, but I was very interested at the very beginning about hypoxia. In fact, I published a paper in 1980, in Radiology. And the title of that paper is “Will hyperthermia conquer the elusive hypoxic cell - implications of heat effects on tumor and normal tissue microcirculation.” There was Window Chamber Data in that paper. So I was interested in that from the beginning and I actually wrote a RO 1 grant, which was funded on the first go around; I was able to bring that grant to Duke to continue that work.
Dr. Lawrence: Because that project really seemed to have developed independently from your work on hyperthermia.
Dr. Dewhirst: It did. I got really interested in the oxygen transport side of that. After Joe retired, they recruited another guy to Arizona by the name of Tim Secomb. Tim was also a theoretician and I worked with Tim on this grant. That grant’s in its 28 or 29 year of funding.
Tim was so helpful to me, because what I learned in doing all the work that we did was that a theoretician like him can really drive the science. We would do a lot of work trying to understand how these various factors influence oxygen transport, because there's so many parameters to influence it that you can't do one simple experiment that can explain what happens. So the way to do it is to gather the data then feed it into a model. And then you can take all that information, put it into a model and make sense out of it. There were some key things that I think we learned. One was the influence of oxygen consumption rate on hypoxia, which was really not appreciated until we published the paper on that a few years back. There are a number of other things that are important along the line. The other thing that we really started to understand by looking at all this was the cycling hypoxia, as well. That wasn't really appreciated as much. I think people thought cycling hypoxia was caused by vascular stasis. And that can happen, but that's not the major cause. The major cause is the instability and red cell flux. We proved that in a paper we published in Cancer Research, I think in 1996, which was been cited like 300 times. I think that was an important discovery.
I can't remember what year it was, but we recruited the other biologist to the department. His name was Chuan Li. He came in the early-90s I think. Chuan was trained by Jack Little. He was a post-doc of Jack’s. He was a very well trained molecular biologist.
Dr. Lawrence: In Boston.
Dr. Dewhirst: In Boston. And it was about that time that fluorescent reporter genes first came on the scene. We started talking about the idea of making a reporter gene that would respond to hypoxia by using the HIF-1 transcription factor. And so Chuan and one of my graduate students engineered some of the first cells that we used. These models formed the basis for the other major discovery which was that radiation and other cytotoxic therapies upregulate the transcriptional activity of HIF-1.
Dr. Lawrence: Yes. That was an important finding.
Dr. Dewhirst: That work was driven by Ben Moeller, my PhD student. He published two back-to-back papers in Cancer Cell.
Dr. Lawrence: I know, we tried very hard to recruit him to our residency program here.
Dr. Dewhirst: In fact, we just published another paper this year on showing a doxorubicin does the same thing in Cancer Research.
Dr. Lawrence: I think it has turned out that this is an important target in cancer therapy in general and I’ve always associated that recognition with your work. You were one of the early developers of that whole field.
Dr. Montana: I want to bring up how you developed this relationship with medical oncologists. Without going into specifics medical oncology, like radiation oncology here in Duke, were not as advanced as they should have been at that time. Duke had a very strong surgical program that led to the designation of Comprehensive Cancer Center but not all the disciplines in the cancer center were as strong as perhaps they should have been. Tell us more about how things happened?
Dr. Dewhirst: The head of the medical oncology division, was Jeff Crawford. He was familiar with what I was doing. He started referring some fellows and residents to me. One of the first people that came into my lab as a fellow was Kim Blackwell. Kim is a medical breast oncologist, and she was interested in angiogenesis. She came into my lab and did some work looking at the antiangiogenic effects of tamoxifen. She got a K08 grant, with me as her mentor, to study that biology. After that she collaborated with me on a breast SPORE project where we followed up on Ben Moeller’s work to look at some of the chemotherapy effects on HIF-1. She also went back to clinic and got more involved in clinical trials. I was very proud of that fact that last year she was named by Time as one of the 100 most influential people in the world. It’s just amazing. She's head of the breast tumor program in the cancer center. But I’ve had others. Herb Hurwitz also worked with me. I was a mentor for him on his K23. I helped him develop an assay to assess the activity of anti-angiogenic drugs using a wound healing assay in patients. And that's how he got the pharmaceutical industry interested in working with him initially. He went on to publish the first New England Journal paper showing that bevacizumab has prolonged survival in metastatic record colorectal cancer.
Dr. Montana: I also want to bring up your very strong collaboration and your lab being open to junior faculty. The names that come to mind are David Brizel and Mitch Anscher.
Dr. Lawrence: I really want to talk with you about the work you did with David Brizel and ask you about imaging too, because the work that you two did together has been fascinating, both a from clinical perspective but also from a basic biology question of what hypoxia means as far as aggressiveness of a tumor versus a therapeutic target. How did you get into the imaging side of that, and I would love to hear you talk about the work with David and with Mitch Anscher.
Dr. Dewhirst: So with David, when he first came to Duke, Lenny encouraged him to try to get some lab experience. David knew about me, because I gave a lecture on tumor hypoxia at the joint center when he was a resident. When he came here, he sought me out, and he actually came to the lab and did a lab project, believe it or not. That lab project was to measure hematocrits in tumor micro vessels. It was a very basic science kind of thing which he did a great job on. We published the result, which ends up being an important paper that has been cited quite a bit (over 50 times). He realized that after doing that his heart was in the clinic, so he went back to the clinic to focus on more translational studies. It was not too long after that, that the Eppendorf oxygen electrode became commercially available. We had a department retreat and they were looking for ideas on what could be done, kind of translational stuff. I suggested we obtain one these devices. Of course that was back when the department had a lot of money, and Lenny just got the check book and wrote a check.
We put that in the clinic and David and I worked together with it initially because it was such a brand new device. The first thing we thought we needed to do was develop quality assurance guidelines and we did some clinical studies to determine how best sample a patient's tumor and get the most meaningful information. But then he started prospective studies on patients with soft tissue sarcoma and head and neck cancer. Those were the two main groups that we looked at. The sarcoma patients were treated very aggressively locally with surgery, radiation and heat. They were part of the hyperthermia program. In that series we had one hundred percent local control rate. There wasn’t one local single failure in that subgroup in which we measured hypoxia. But overall survival of patients with hypoxic tumors was much worse. The paper has been cited about 900 times.
Dr. Lawrence: I cite that paper when trying to explain hypoxia to our residents. It's a target, and it still maybe a target, but it may just describe the tumor biology.
Dr. Dewhirst: Not completely, I don't think. But I think hypoxia is important, for sure.
Dr. Montana: I also want to bring up the role of some of the people that you collaborated with, like John Harrelson.
Dr. Dewhirst: Yes. John Harrelson.
Dr. Montana: John Harrelson was an orthopedic surgeon who had a particular interest in soft tissue sarcomas.
Dr. Dewhirst: If it hadn’t been for John, we wouldn’t have been able to do that stuff. That's for sure.
Dr. Montana: And David.
Dr. Dewhirst: Yes. With David, we were able to accrue a study in patients with head and neck cancer that was large enough to be able to do multi-variant analysis to show that hypoxia was an independent projector of local tumor control after radiotherapy.
I have to say that, perhaps the more interesting side of all this science, was looking at what we could do to predict metastasis. And this is what got us into MR imaging. In the early 1990’s 31-P MR spectroscopy was of interest, because it gave information about tumor metabolism. We were very much in the front end of that. In fact, a lot of our early work was what stimulated later UO1 grants on this idea of using 31-P MRS to predict outcomes. We did some initial work looking at how 31-P MR might predict response rate and duration local control both in humans and dogs with cancer. Later on, we started looking at metastasis, and one of the things that we projected ahead of time was that PME/PDE ratio, which reflects lipid turnover rate, might predict metastasis rate. It turned out that the hypothesis was true in both human and canine patients with soft tissue sarcomas. That ratio predicts for higher likelihood for development of metastasis. I think this was an important paper as a proof of principle, but 31-P MR is not practical, clinically. But along the same lines, we started looking at lactate and lactate, I think, is tractable. We subsequently showed in head and neck cancer that lactate concentrations predicted metastasis and overall survival, but did not predict the local control. Lactate was not a surrogate for hypoxia at all.
Dr. Lawrence: The whole area of molecular biology and genomics has in some ways killed off a lot of tumor biologists. Somehow you managed to survive. What's the secret?
Dr. Dewhirst: I blended the two. Seriously. I published a paper in Seminars in Radiation recently on this subject. I think that genomics do not replace tumor physiology. And in fact, what imaging can do, particularly physiologic imaging, is it can give you directed ways to look at genomic data. With genomic or full sequencing data, the false positive rate is extremely high. So you have to use really, really low p-values to come up with anything. You may miss important information, but you don't know which rock to look under.
And so that's what we've used. We've used the imaging to help us focus our ideas, so that we can make it easier to look at genomic data. I have published one paper on dog sarcomas in Clinical Cancer Research, where we looked at ADC and genomic data. I have a paper that is in review that combines DCE-MRI data with genomics in patients with locally advanced breast cancer. It's a chicken and egg supposed issue as to whether or not physiology drives the genomics or the genomics drives the physiology. But the two are inexorably linked one way or the other.
Dr. Lawrence: That's great because a lot of tumor biologists did not make that leap that you made, and I think it's been worse for our field, and for oncology in general, that very few people have been able to combine things. Can I be even more philosophical and ask you what advice would you give to young people who are trying to pick a field to focus on for oncologic related science. What would you advise them today?
Dr. Dewhirst: Actually I give this advice pretty often. What I tell people is that you need to develop your unique skill set. That's what set my trajectory. The window chamber was what made my career, no question about that.
Dr. Lawrence: It is a beautiful technique. It was a beautiful technique and particularly you used it so well early on when no one else is using that.
Dr. Dewhirst: I think sometimes you can't develop a new technique, but if you get a unique combination of skills that makes you unique, in a sense, that you can ask questions other people can't because you have that combination of skill. So that's one of the things that I'm really trying to teach people about, so I really push people towards K-grants, where they can get that additional training in ancillary areas that make them have unique ability to look at things. That's my advice. The other thing is to learn how to write grants. That's not simple, and it's not something that you can just pick up. It takes training to learn how to do that, which is what we do in my dean’s office, where I am the Associate Dean for Faculty Mentoring.
Dr. Montana: Mark, looking back on your prolific and successful academic career, tell us about what has given you the most satisfaction?
Dr. Dewhirst: Oh, it's the people I mentored for sure.
Dr. Montana: Yeah.
Dr. Dewhirst: You know, papers are a dime a dozen.
Dr. Montana: For you maybe.
Dr. Dewhirst: There are a few papers I'm really proud of. But it's the people that I mentored. I even stay in touch with most of them, and they send me emails, and we communicate back and forth. They're my extended family. I get drive and tremendous joy out of that.
Dr. Montana: Well, they do too Mark. Many people the institution and our department owe a lot to you.
Dr. Dewhirst: Well, thank you. They helped me too, so it's a two-way street. People challenged me, so that's always good.
Dr. Lawrence: You're so successful as a biologist in working with physicians. I can hardly think of anyone who's done better than you have. What's the secret there? How do you build those biology clinical teams? They’re so hard to build and you've done it successfully multiple times. What's the secret?
Dr. Dewhirst: You have to put on the clinician’s shoe. You have to try to learn how the clinicians think and what their issues are. And I think I learned that by going down and being in the clinic for a few years when I first came here. I think that's really important, because otherwise it's difficult to appreciate and communicate with clinicians in a way that they can really understand where things might go. The other thing that I've always emphasized in everything I do, is to say to myself, and to the person I'm working with, “How can we use this information clinically?” That's always on the top of my mind. But sometimes, it doesn't work out that way, but it’s always there at the front saying what is the relevance of this observation to the clinic? And I always challenge people that way. Engineers and the like, everybody. I think that, that's important.
Dr. Montana: I also think that your clinical background has put you in a privileged position to understand what the clinicians go through and gives more meaning to your research and to all your academic activities.
Dr. Dewhirst: I did have the experience of working for five years doing a referral radiation oncology practice, which definitely gave me a leg up on that.
I came into this business with the idea of trying to make human medicine better. By the way when I left Colorado, I could have gone to a veterinary school. But, I made a conscious decision to go to medical schools because I felt that I could make an impact. Whereas in a veterinary school, you might help pets, which is nice, and it’s not that I don't or would not want to do that, but I really wanted to make an impact on humans.
Dr. Lawrence: Well, you certainly have.
Dr. Montana: You have and you continue to do so. Your research will continue to impact on the lives of human beings.
Dr. Dewhirst: Thank you. There’s one last thing, and it is an extremely important comment. And that's my wife Nancy. I wouldn't be here if it wasn’t for her. She's my partner. I’m an editor for a journal, and she's the managing editor of our journal. I'm editor in-chief and she tells me what to do and I do it. But I mean, she is just fantastic.
Dr. Lawrence: And that's a beautiful and important comment, because a lot of people think that it's career versus personal life. And that's a beautiful thing that you have managed to integrate things.
Dr. Montana: I have known Nancy a number of years.
Dr. Dewhirst: You’ve known her longer than I have.
Dr. Montana: I met Nancy when she was a nurse in the head and neck clinic at the University of North Carolina (UNC). She was a wonderful nurse but even more than that, she is a wonderful human being. I will say that not enough good can be said about Nancy. Mark you are certainly a lucky man.
Dr. Dewhirst: That's true.
Dr. Montana: She's fantastic.
Dr. Dewhirst: She's the love of my life for sure.
Dr. Montana: Thank you Mark.
Dr. Dewhirst: Okay. My pleasure. I'm honored you have done this. Thank you so much and it's just fantastic that you agreed to do it.
Dr. Montana: It's just been great to work with you all these years. On behalf of the History Committee, Ted and I thank you sincerely for allowing us to interview you.
Dr. Dewhirst: Thank you very much.
Dr. Dewhirst: Okay. Well, I was born in what's called the “little apple”, which is Manhattan, Kansas, in 1949. My father was a graduate student at that time in animal sciences. After he received his PhD, we moved to a Tucson. We moved to Tucson when I was 7 years old. I was in second grade I believe. I think of Tucson as my hometown. I grew up there and went to high school. Since my father was on the faculty of the University of Arizona in Tucson, Arizona, I had the options to go to one of the schools in Arizona; this was strongly encouraged because faculty had a tuition benefit. I went to Northern Arizona University for a year and had a lot of fun up there, but I realized if I was going to do anything seriously, I needed to come back to Tucson and go to the University of Arizona. I spent the last three years at the University of Arizona and graduated from there in 1971, with a bachelor's degree in chemistry.
Dr. Lawrence: Did you do any research during your undergraduate work that got you interested in your future career or mainly stick with the course work?
Dr. Dewhirst: No. I did do research. I worked in several laboratories during that period of time, but having a father who is a scientist also stimulated me to be interested in research. He was in parasitology, and I can remember when I was five years old going out in the fields in Manhattan collecting fecal samples to look for worms. So I kind of got the bug, if you will.
Dr. Montana: Just like that.
Dr. Dewhirst: I did undergraduate research in the chemistry department. I also worked in the agronomy and plant pathology departments throughout my undergraduate studies.
Dr. Montana: And then you went to Colorado?
Dr. Dewhirst: I did. I actually started out as a pre-med in the chemistry department, and what I discovered was that the pre-meds there were a bit obnoxious.
Dr. Lawrence: Did you think about becoming a practicing veterinarian?
Dr. Dewhirst: No. When I applied I said I was interested in research. In fact, I was telling my father, when I decided to go, that I really thought that it would be interesting to study diseases in pet's as models for humans. I had no idea what I was talking about at the time, but it turned out to be a terrific career path.
Dr. Lawrence: I have always thought the best research degree was the veterinary degree, for that exact reason.
Dr. Dewhirst: So, I went to Colorado State and had a summer job working for Ed Gillette. That is what stimulated me to pursue a career in cancer research.
Dr. Lawrence: Ah, perfect.
Dr. Dewhirst: That’s how it happened, because up until that time I had lots of jobs and they were all kind of interesting. But when I started studying radiation oncology, and oncology in general, I knew I was hooked because I couldn't stop reading about it. It was the most interesting thing that I had ever done.
Dr. Montana: Was Ed at Colorado then?
Dr. Dewhirst: Yes, he was.
Dr. Montana: He died not too many years ago.
Dr. Dewhirst: Yes. Their department was certainly, I'd say, world famous. The department of radiation biology was in a position of prominence back in the 70s. The department was started in the early 1960s. So by the time I was there it was very well established and very well known.
Dr. Lawrence: I think it’s one of the best programs in the world in animal radiation biology and understanding, not just cells and culture, but actual patients.
Dr. Dewhirst: Yes. And that happened because Ed did a Sabbatical with Herman Suit. He was at MD Anderson. And Rod Withers was there at that time.
They had many discussions about how he could use pet animal tumors to learn more about radiation oncology. He took those ideas back to Colorado with a vision of creating an animal tumor center. I was in on it from the very beginning, along with Don Thrall and a third veterinarian, named Patrick Gavin. We were there at the very beginning of the animal tumor center. This was back when the other clinicians in the hospital who were doing oncology would hide patients from Ed, because they didn't want him to irradiate them. He had a bunch of undergraduate technicians that he hired, they would go cruise through the wards looking for potential cancer patient that could be treated with radiation therapy. We called them the “tumor beavers”. Now there is a specialty board for veterinary radiation oncology and it is a very well respected field. So times change that's for sure.
Dr. Montana: So Mark, you went back to Tucson, right?
Dr. Dewhirst: Yes, I did.
Dr. Lawrence: Wait a second, you did the veterinarian’s degree but then you decided to go graduate school, right?
Dr. Dewhirst: I did. I got a PhD at Colorado State, with Ed. And because I knew I wanted to do a PhD, and I had a family at that time, and I really liked Ed, and so it just seemed to be the right thing to do. So I stayed there and did a PhD with him. When I was in graduate school, a relatively famous radiation oncologist came to CSU on Sabbatical; his name was Max Boone. Max had been the prior chair of radiation oncology in Arizona. We were in the same lab working together and we struck up a friendship. He was one of the most brilliant men I've ever met. So when I decided to start looking for post docs, I interviewed at Washington University, with the guy named Fred Valleriote and George Hahn at Stanford. And then I interviewed with Max. I ended up going back to Arizona because of my friendship with Max and for economic reasons. They were willing to offer me a bit more money and I, again, had a family. But at the time, both Stanford and the Arizona group had program project grants in hyperthermia, and both programs were treating pets with cancer with heat.
Dr. Lawrence: You just answered my question on how you got started in hyperthermia.
Dr. Dewhirst: Yes. I was recruited to do this. I was always interested in the idea of running clinical trials in pets, particularly after I learned about veterinary oncology. I just thought it would be really interesting to do. So, it was a perfect job for me, I loved it. Over the five years that I was there in Arizona I ran a randomized trial. It was the first randomized trial comparing radiation therapy alone to radiation plus heat. I accrued 250 pets under that trial, in five years.
Dr. Montana: So, Jim Oleson was there at the time?
Dr. Dewhirst: Jim was there. That's how we met. It was a great time. Both Jim and I learned a lot by being a part of that program. Eugene Garner was head of it. Toward the end of the five years, though, I began to be very dissatisfied with the way it was arranged. It really had to deal with the fact that I was running an oncology practice out of a medical school with no infrastructure. A lot of these pets, as you can imagine, had other co-morbidities and I didn't have any support to help them with their other health problems. I was on call 24/7. It was just killing me. In the end I had to do something different. I approached the medical school about the idea of buying a clinical practice that was nearby and was up for sale. I proposed to upgrade it and do oncology trials at the facility. In doing so I could hire the right kind of people to help me. However, the medical school was not interested in that. So I started looking around for jobs. Ironically, Jim started looking for jobs at the same time. He wanted a job where he could have more authority over a research program. My wife and I happened to go over to Jim’s house for dinner one night. Just by chance, I happened to mention that I was looking to go elsewhere. Neither one of us knew at the time. So he said we should try to work it out so we could go together. I thought, “Yeah, sure, that will happen.”
Dr. Lawrence: That would’ve been difficult. Wow.
Dr. Dewhirst: That’s how it happened though. I interviewed at Wisconsin, which had a veterinary school and medical school on the same campus. I also interviewed at NIH for a job.
Dr. Montana: Eli was there at the time.
Dr. Dewhirst: But the Duke job was by far the most attractive. The package they put together for us was incredible. I was so impressed with the demeanor of the place and also their tremendous resources that they had, particularly in imaging.
Dr. Lawrence: Who was the chair at that time?
Dr. Montana: It was in transition at that time. Len had just come here to Duke.
Dr. Dewhirst: He was the division chief at that time
Dr. Montana: Len had already paved the way for it to become a department.
Dr. Dewhirst: Yes. He had just struck a deal that if he showed that he could make money they would let him create a separate department from radiology. That didn't take very long. Charles Putnam was the chair of radiology at that time.
Dr. Lawrence: Okay. So it was the chair of radiology who had recruited you into the section of radiation oncology, is that how it worked?
Dr. Dewhirst: Yes, into this division.
Dr. Montana: Dr. Putman, the chair of the radiology department here at Duke, had been the member of the radiology department at Yale, and knew Len Prosnitz well and was very influential in getting Len to come here to Duke to head the division of radiation oncology that became a department soon thereafter.
Dr. Dewhirst: Yes. That's how it happened. And then Len decided he wanted to build a world class research group. I think he thought about a lot of options at that time. And at that time, hyperthermia was pretty popular, so he recruited Jim. Jim said, “Well, I can't come unless Mark comes.” That's how I ended coming here.
Dr. Lawrence: So we're now around 1984, is that about right?
Dr. Dewhirst: Yes, I came here in 1984.
Dr. Lawrence: Yes, I'm looking at your CV and your first appointment actually was in the department of radiology, so this must be in the transition of radiation oncology becoming a new department.
Dr. Dewhirst: Right.
Dr. Lawrence: So you then just continued to work in hyperthermia.
Dr. Dewhirst: We built on what we did in Arizona through an incredibly large startup package that we got from the cancer center, the department and the dean. Our charge was to develop a program project grant. We started working on this goal in 1984, and got it funded in 1987.
Dr. Lawrence: That's very quick when it's from the ground up.
Dr. Montana: You also were successful in recruiting Thad Samulski around at that time.
Dr. Dewhirst: We did. We recruited Thad Samulski here and Scott Clegg who is another engineer. Thad was really a physicist, but we had Thad and Scott. Thad just absolutely fundamental in getting everything done because, although Jim Oleson had a background in engineering, he couldn't make machines run and do all the infrastructure for QA and QC and so forth.
Dr. Montana: Thad had been at a Stanford working in hyperthermia.
Dr. Dewhirst: Right. He worked with George Hahn.
Dr. Lawrence: I interviewed at the University of Arizona out of my residency in 1986, and Tom Cetas was still there. But they were still mourning the loss of you and Jim.
Dr. Dewhirst: I think the other key to the success of our program in the long run was our association with NC State. So we continued our work with spontaneous animal tumors up until our program stopped in 2009. The fact that we had access to these animal patients was really key because we were able to do so many things with them that we could just never do in human subjects. We learned so much. In a number of cases we have avoided running costly clinical trials in humans by finding out things in the pets and seeing clearly it wasn't going to work. I actually gave a lecture last weekend at the Veterinary Cancer Society meeting which was in Ashville. And they asked me to review that experience. It turned out, over those years, we published over 80 papers involving pets with cancer. I think it was 1,200 citations, or something like that. It's a tribute to what Ed Gillette taught both Don Thrall and I. I feel very proud of that part of my career. I really do.
Dr. Montana: One of the impressive things when you, Jim Oleson and Thad Samulski came here is that you did not operate as a separate division or enclave outside of the mainstream of the clinical practice. You were very present at the conferences and all functions of the department. You were all very receptive to medical students, residents, and junior members of the faculty. You all supported and encouraged everybody to engage in research.
Dr. Dewhirst: I felt it was very important. I used to go to the grand rounds all the time. The other thing I did, actually with Jim at the beginning, was to go into the clinic and shadowed Jim as he worked with patients, because I wanted to understand and support what they were going through. He actually helped with some of the dogs to, so it was kind of a cross-fertilization kind of thing.
And, and what I have to tell you which is anecdotal also, a couple of funny stories about that. One was that working with patients was first at first very disconcerting because they talked back to me. It was a strange feeling to have a patient talk to me when I walk into the room. It’s really funny, since I was a veterinarian, one patient was asking me if I was going to him a rabies shot.
We treated the first dog with cancer within a month of my arrival at Duke. It was a dog with prostate cancer and we did some heat and radiation treatment of this tumor. We used to have this cage which was covered up and was on wheels, and we’d put a sheet over it and we wheeled that dog into the area where the hyperthermia equipment was located. My technician opened the lid on that thing and walked away and then the dog, of course, jumps out. It ran down the hall into the middle of the waiting area, and here comes Len Prosnitz walking down the hall. I'm going, “Oh my God, he's gonna fire me.” The dog jumped up on his leg, wanting to be petted. Fortunately for me, Len liked dogs. We penned up the dog and put him back to where he belonged. I enjoyed being involved in the clinic and I felt like that was where I should be.
Dr. Montana: The basic sciences research program in our department at Duke exploded during that period of time. We always admired your ability to collaborate with people outside the department. Tell us more about that or some of the people that you began to develop research programs with.
Dr. Dewhirst: Thank you. At its height, the hyperthermia program had, I think, eight different departments involved across the medical school and the main campus. We had people from the engineering school as well as people from all kinds of the departments in the medical school. Pathology and a lot of radiology faculty. There were people from biomedical engineering, electrical engineering and microbiology. One of the things I used to do was to try to think outside the box, and invite other people to attend our research retreats. One of the things that came out of it was the idea that we might come up with a way to use heat to trigger drug delivery. I knew a guy who knew how to make liposomes. He was at the engineering school. I invited him to come during the retreat one time and I said, “It would be very interesting if you could make a liposome that was thermally sensitive in the clinically relevant temperature range.” This was an idea presented in literature already, but it was not practical, because the release temperature was too high. So he went back to his lab and invented a liposome that would actually release drug within the clinically relevant temperature range. I know you know about this Ted, because you handled the paper that we published in cancer research.
Dr. Lawrence: Yes, I did. It was really a beautiful paper. The reviewers really loved it.
Dr. Dewhirst: Oh, good. That was the real paradigm shift to just say that you could do something that would release drug inside the blood vessel. So, you kind of essentially have the equivalent of a local drug infusion in the tumor itself.
Dr. Lawrence: That leads to me next question. How did you go from hyperthermia to microvasculature. Because you've made so many contributions outside of hyperthermia, especially by developing the window chamber model to study the microvasculature. I wonder if you could talk about that a little bit and how you got into that.
Dr. Dewhirst: My own PhD thesis had to do with radiation effects on lymphocytes. And I went to Arizona with the express idea in mind that I was going to continue that work, but I hadn’t been there too long, and Gene Garner came to me and he said, “You are a veterinarian, right? Well, you must know some physiology.” I said, “Well, I took a course in vet school. I’m not an expert in physiology”. He said, “Well, I want you to meet this chemical engineer. His name is Joseph Gross. And he has this window chamber thing. He’s looking for somebody to help him with it.” Joe was a chemical engineer; he was really theoretician. He studied drug transport and did modelling and stuff like that. But he had taken the original Algire chamber and redesigned it to be made out of metal instead of plastics, so that it was resistant to crushing artifact that would artificially shut down blood flow. Joe made one out of anodized aluminum, and he co-engineered it with another guy. But he didn't have anybody to use it because he didn't know about biology really. So, I went over and I saw this thing and I thought to myself that “this was a freaking gold mine.” “If I don’t take this and do something with it, I'm just crazy.” I learned how to do the surgery. I went to California, to UCSD where there was a group that did a lot of intravital microscopy. That’s how I learned to do that. I then brought that technology back to Tucson and started working with it. Some of the initial work I did was actually looking in heat effects on perfusion and so forth, but I was very interested at the very beginning about hypoxia. In fact, I published a paper in 1980, in Radiology. And the title of that paper is “Will hyperthermia conquer the elusive hypoxic cell - implications of heat effects on tumor and normal tissue microcirculation.” There was Window Chamber Data in that paper. So I was interested in that from the beginning and I actually wrote a RO 1 grant, which was funded on the first go around; I was able to bring that grant to Duke to continue that work.
Dr. Lawrence: Because that project really seemed to have developed independently from your work on hyperthermia.
Dr. Dewhirst: It did. I got really interested in the oxygen transport side of that. After Joe retired, they recruited another guy to Arizona by the name of Tim Secomb. Tim was also a theoretician and I worked with Tim on this grant. That grant’s in its 28 or 29 year of funding.
Tim was so helpful to me, because what I learned in doing all the work that we did was that a theoretician like him can really drive the science. We would do a lot of work trying to understand how these various factors influence oxygen transport, because there's so many parameters to influence it that you can't do one simple experiment that can explain what happens. So the way to do it is to gather the data then feed it into a model. And then you can take all that information, put it into a model and make sense out of it. There were some key things that I think we learned. One was the influence of oxygen consumption rate on hypoxia, which was really not appreciated until we published the paper on that a few years back. There are a number of other things that are important along the line. The other thing that we really started to understand by looking at all this was the cycling hypoxia, as well. That wasn't really appreciated as much. I think people thought cycling hypoxia was caused by vascular stasis. And that can happen, but that's not the major cause. The major cause is the instability and red cell flux. We proved that in a paper we published in Cancer Research, I think in 1996, which was been cited like 300 times. I think that was an important discovery.
I can't remember what year it was, but we recruited the other biologist to the department. His name was Chuan Li. He came in the early-90s I think. Chuan was trained by Jack Little. He was a post-doc of Jack’s. He was a very well trained molecular biologist.
Dr. Lawrence: In Boston.
Dr. Dewhirst: In Boston. And it was about that time that fluorescent reporter genes first came on the scene. We started talking about the idea of making a reporter gene that would respond to hypoxia by using the HIF-1 transcription factor. And so Chuan and one of my graduate students engineered some of the first cells that we used. These models formed the basis for the other major discovery which was that radiation and other cytotoxic therapies upregulate the transcriptional activity of HIF-1.
Dr. Lawrence: Yes. That was an important finding.
Dr. Dewhirst: That work was driven by Ben Moeller, my PhD student. He published two back-to-back papers in Cancer Cell.
Dr. Lawrence: I know, we tried very hard to recruit him to our residency program here.
Dr. Dewhirst: In fact, we just published another paper this year on showing a doxorubicin does the same thing in Cancer Research.
Dr. Lawrence: I think it has turned out that this is an important target in cancer therapy in general and I’ve always associated that recognition with your work. You were one of the early developers of that whole field.
Dr. Montana: I want to bring up how you developed this relationship with medical oncologists. Without going into specifics medical oncology, like radiation oncology here in Duke, were not as advanced as they should have been at that time. Duke had a very strong surgical program that led to the designation of Comprehensive Cancer Center but not all the disciplines in the cancer center were as strong as perhaps they should have been. Tell us more about how things happened?
Dr. Dewhirst: The head of the medical oncology division, was Jeff Crawford. He was familiar with what I was doing. He started referring some fellows and residents to me. One of the first people that came into my lab as a fellow was Kim Blackwell. Kim is a medical breast oncologist, and she was interested in angiogenesis. She came into my lab and did some work looking at the antiangiogenic effects of tamoxifen. She got a K08 grant, with me as her mentor, to study that biology. After that she collaborated with me on a breast SPORE project where we followed up on Ben Moeller’s work to look at some of the chemotherapy effects on HIF-1. She also went back to clinic and got more involved in clinical trials. I was very proud of that fact that last year she was named by Time as one of the 100 most influential people in the world. It’s just amazing. She's head of the breast tumor program in the cancer center. But I’ve had others. Herb Hurwitz also worked with me. I was a mentor for him on his K23. I helped him develop an assay to assess the activity of anti-angiogenic drugs using a wound healing assay in patients. And that's how he got the pharmaceutical industry interested in working with him initially. He went on to publish the first New England Journal paper showing that bevacizumab has prolonged survival in metastatic record colorectal cancer.
Dr. Montana: I also want to bring up your very strong collaboration and your lab being open to junior faculty. The names that come to mind are David Brizel and Mitch Anscher.
Dr. Lawrence: I really want to talk with you about the work you did with David Brizel and ask you about imaging too, because the work that you two did together has been fascinating, both a from clinical perspective but also from a basic biology question of what hypoxia means as far as aggressiveness of a tumor versus a therapeutic target. How did you get into the imaging side of that, and I would love to hear you talk about the work with David and with Mitch Anscher.
Dr. Dewhirst: So with David, when he first came to Duke, Lenny encouraged him to try to get some lab experience. David knew about me, because I gave a lecture on tumor hypoxia at the joint center when he was a resident. When he came here, he sought me out, and he actually came to the lab and did a lab project, believe it or not. That lab project was to measure hematocrits in tumor micro vessels. It was a very basic science kind of thing which he did a great job on. We published the result, which ends up being an important paper that has been cited quite a bit (over 50 times). He realized that after doing that his heart was in the clinic, so he went back to the clinic to focus on more translational studies. It was not too long after that, that the Eppendorf oxygen electrode became commercially available. We had a department retreat and they were looking for ideas on what could be done, kind of translational stuff. I suggested we obtain one these devices. Of course that was back when the department had a lot of money, and Lenny just got the check book and wrote a check.
We put that in the clinic and David and I worked together with it initially because it was such a brand new device. The first thing we thought we needed to do was develop quality assurance guidelines and we did some clinical studies to determine how best sample a patient's tumor and get the most meaningful information. But then he started prospective studies on patients with soft tissue sarcoma and head and neck cancer. Those were the two main groups that we looked at. The sarcoma patients were treated very aggressively locally with surgery, radiation and heat. They were part of the hyperthermia program. In that series we had one hundred percent local control rate. There wasn’t one local single failure in that subgroup in which we measured hypoxia. But overall survival of patients with hypoxic tumors was much worse. The paper has been cited about 900 times.
Dr. Lawrence: I cite that paper when trying to explain hypoxia to our residents. It's a target, and it still maybe a target, but it may just describe the tumor biology.
Dr. Dewhirst: Not completely, I don't think. But I think hypoxia is important, for sure.
Dr. Montana: I also want to bring up the role of some of the people that you collaborated with, like John Harrelson.
Dr. Dewhirst: Yes. John Harrelson.
Dr. Montana: John Harrelson was an orthopedic surgeon who had a particular interest in soft tissue sarcomas.
Dr. Dewhirst: If it hadn’t been for John, we wouldn’t have been able to do that stuff. That's for sure.
Dr. Montana: And David.
Dr. Dewhirst: Yes. With David, we were able to accrue a study in patients with head and neck cancer that was large enough to be able to do multi-variant analysis to show that hypoxia was an independent projector of local tumor control after radiotherapy.
I have to say that, perhaps the more interesting side of all this science, was looking at what we could do to predict metastasis. And this is what got us into MR imaging. In the early 1990’s 31-P MR spectroscopy was of interest, because it gave information about tumor metabolism. We were very much in the front end of that. In fact, a lot of our early work was what stimulated later UO1 grants on this idea of using 31-P MRS to predict outcomes. We did some initial work looking at how 31-P MR might predict response rate and duration local control both in humans and dogs with cancer. Later on, we started looking at metastasis, and one of the things that we projected ahead of time was that PME/PDE ratio, which reflects lipid turnover rate, might predict metastasis rate. It turned out that the hypothesis was true in both human and canine patients with soft tissue sarcomas. That ratio predicts for higher likelihood for development of metastasis. I think this was an important paper as a proof of principle, but 31-P MR is not practical, clinically. But along the same lines, we started looking at lactate and lactate, I think, is tractable. We subsequently showed in head and neck cancer that lactate concentrations predicted metastasis and overall survival, but did not predict the local control. Lactate was not a surrogate for hypoxia at all.
Dr. Lawrence: The whole area of molecular biology and genomics has in some ways killed off a lot of tumor biologists. Somehow you managed to survive. What's the secret?
Dr. Dewhirst: I blended the two. Seriously. I published a paper in Seminars in Radiation recently on this subject. I think that genomics do not replace tumor physiology. And in fact, what imaging can do, particularly physiologic imaging, is it can give you directed ways to look at genomic data. With genomic or full sequencing data, the false positive rate is extremely high. So you have to use really, really low p-values to come up with anything. You may miss important information, but you don't know which rock to look under.
And so that's what we've used. We've used the imaging to help us focus our ideas, so that we can make it easier to look at genomic data. I have published one paper on dog sarcomas in Clinical Cancer Research, where we looked at ADC and genomic data. I have a paper that is in review that combines DCE-MRI data with genomics in patients with locally advanced breast cancer. It's a chicken and egg supposed issue as to whether or not physiology drives the genomics or the genomics drives the physiology. But the two are inexorably linked one way or the other.
Dr. Lawrence: That's great because a lot of tumor biologists did not make that leap that you made, and I think it's been worse for our field, and for oncology in general, that very few people have been able to combine things. Can I be even more philosophical and ask you what advice would you give to young people who are trying to pick a field to focus on for oncologic related science. What would you advise them today?
Dr. Dewhirst: Actually I give this advice pretty often. What I tell people is that you need to develop your unique skill set. That's what set my trajectory. The window chamber was what made my career, no question about that.
Dr. Lawrence: It is a beautiful technique. It was a beautiful technique and particularly you used it so well early on when no one else is using that.
Dr. Dewhirst: I think sometimes you can't develop a new technique, but if you get a unique combination of skills that makes you unique, in a sense, that you can ask questions other people can't because you have that combination of skill. So that's one of the things that I'm really trying to teach people about, so I really push people towards K-grants, where they can get that additional training in ancillary areas that make them have unique ability to look at things. That's my advice. The other thing is to learn how to write grants. That's not simple, and it's not something that you can just pick up. It takes training to learn how to do that, which is what we do in my dean’s office, where I am the Associate Dean for Faculty Mentoring.
Dr. Montana: Mark, looking back on your prolific and successful academic career, tell us about what has given you the most satisfaction?
Dr. Dewhirst: Oh, it's the people I mentored for sure.
Dr. Montana: Yeah.
Dr. Dewhirst: You know, papers are a dime a dozen.
Dr. Montana: For you maybe.
Dr. Dewhirst: There are a few papers I'm really proud of. But it's the people that I mentored. I even stay in touch with most of them, and they send me emails, and we communicate back and forth. They're my extended family. I get drive and tremendous joy out of that.
Dr. Montana: Well, they do too Mark. Many people the institution and our department owe a lot to you.
Dr. Dewhirst: Well, thank you. They helped me too, so it's a two-way street. People challenged me, so that's always good.
Dr. Lawrence: You're so successful as a biologist in working with physicians. I can hardly think of anyone who's done better than you have. What's the secret there? How do you build those biology clinical teams? They’re so hard to build and you've done it successfully multiple times. What's the secret?
Dr. Dewhirst: You have to put on the clinician’s shoe. You have to try to learn how the clinicians think and what their issues are. And I think I learned that by going down and being in the clinic for a few years when I first came here. I think that's really important, because otherwise it's difficult to appreciate and communicate with clinicians in a way that they can really understand where things might go. The other thing that I've always emphasized in everything I do, is to say to myself, and to the person I'm working with, “How can we use this information clinically?” That's always on the top of my mind. But sometimes, it doesn't work out that way, but it’s always there at the front saying what is the relevance of this observation to the clinic? And I always challenge people that way. Engineers and the like, everybody. I think that, that's important.
Dr. Montana: I also think that your clinical background has put you in a privileged position to understand what the clinicians go through and gives more meaning to your research and to all your academic activities.
Dr. Dewhirst: I did have the experience of working for five years doing a referral radiation oncology practice, which definitely gave me a leg up on that.
I came into this business with the idea of trying to make human medicine better. By the way when I left Colorado, I could have gone to a veterinary school. But, I made a conscious decision to go to medical schools because I felt that I could make an impact. Whereas in a veterinary school, you might help pets, which is nice, and it’s not that I don't or would not want to do that, but I really wanted to make an impact on humans.
Dr. Lawrence: Well, you certainly have.
Dr. Montana: You have and you continue to do so. Your research will continue to impact on the lives of human beings.
Dr. Dewhirst: Thank you. There’s one last thing, and it is an extremely important comment. And that's my wife Nancy. I wouldn't be here if it wasn’t for her. She's my partner. I’m an editor for a journal, and she's the managing editor of our journal. I'm editor in-chief and she tells me what to do and I do it. But I mean, she is just fantastic.
Dr. Lawrence: And that's a beautiful and important comment, because a lot of people think that it's career versus personal life. And that's a beautiful thing that you have managed to integrate things.
Dr. Montana: I have known Nancy a number of years.
Dr. Dewhirst: You’ve known her longer than I have.
Dr. Montana: I met Nancy when she was a nurse in the head and neck clinic at the University of North Carolina (UNC). She was a wonderful nurse but even more than that, she is a wonderful human being. I will say that not enough good can be said about Nancy. Mark you are certainly a lucky man.
Dr. Dewhirst: That's true.
Dr. Montana: She's fantastic.
Dr. Dewhirst: She's the love of my life for sure.
Dr. Montana: Thank you Mark.
Dr. Dewhirst: Okay. My pleasure. I'm honored you have done this. Thank you so much and it's just fantastic that you agreed to do it.
Dr. Montana: It's just been great to work with you all these years. On behalf of the History Committee, Ted and I thank you sincerely for allowing us to interview you.
Dr. Dewhirst: Thank you very much.
